CDCA7-associated global aberrant DNA hypomethylation translates to localized, tissue-specific transcriptional responses.

Disruption of cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA methylation levels across multiple tissues in vivo. A pathogenic Cdca7 missense variant leads to the formation of large, aberrantly hypomethylated domains overlapping with the B genomic compartment but without affecting the deposition of H3K9 trimethylation (H3K9me3). CDCA7-associated aberrant DNA hypomethylation translated to localized, tissue-specific transcriptional dysregulation that affected large gene clusters. In the brain, we identify CDCA7 as a transcriptional repressor and epigenetic regulator of clustered protocadherin isoform choice. Increased protocadherin isoform expression frequency is accompanied by DNA methylation loss, gain of H3K4 trimethylation (H3K4me3), and increased binding of the transcriptional regulator CCCTC-binding factor (CTCF). Overall, our in vivo work identifies a key role for CDCA7 in safeguarding tissue-specific expression of gene clusters via the DNA methylation pathway.

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome.

DNA methylation is an epigenetic modification essential for normal mammalian development. Initially associated with gene silencing, more diverse roles for DNA methylation in the regulation of gene expression patterns are increasingly being recognized. Some of these insights come from studying the function of genes that are mutated in human diseases characterized by abnormal DNA methylation landscapes. The first disorder to be associated with congenital defects in DNA methylation was Immunodeficiency, Centromeric instability, Facial anomalies syndrome (ICF). The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease. Here, we discuss recent progress in understanding the molecular interactions between these genes and consider current evidence for how aberrant DNA methylation may contribute to the abnormal phenotype present in ICF syndrome patients.

Making headway towards understanding how epigenetic mechanisms contribute to early-life effects.

It has become clear that in addition to the DNA sequence there is another layer of information, termed epigenetic modifications, that can influence phenotypes and traits. In particular, environmental epigenomics, which addresses the effect of the environment on the epigenome and human health, is becoming an area of great interest for many researchers working in different scientific fields. In this review, we will consider the current evidence that early-life environmental signals can have long-term effects on the epigenome. We will further evaluate how recent technological advances may enable us to unravel the molecular mechanisms underlying these phenomena, which will be crucial for understanding heritability in health and disease. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.

Relevance of vitamin D receptor target genes for monitoring the vitamin D responsiveness of primary human cells.

Vitamin D3 has transcriptome- and genome-wide effects and activates, via the binding of its metabolite 1α,25-dihydroxyvitamin D3 to the transcription factor vitamin D receptor (VDR), several hundred target genes. Using samples from a 5-month vitamin D3 intervention study (VitDmet), we recently reported that the expression of 12 VDR target genes in peripheral blood mononuclear cells (PBMCs) as well as 12 biochemical and clinical parameters of the study participants are significantly triggered by vitamin D3. In this study, we performed a more focused selection of further 12 VDR target genes and demonstrated that changes of their mRNA expression in PBMCs of VitDmet subjects significantly correlate with alterations of 25-hydroxyvitamin D3 serum levels. Network and self-organizing map analysis of these datasets together with that of the other 24 parameters was followed by relevance calculations and identified changes in parathyroid hormone serum levels and the expression of the newly selected genes STS, BCL6, ITGAM, LRRC25, LPGAT1 and TREM1 as well as of the previously reported genes DUSP10 and CD14 as the most relevant parameters for describing vitamin D responsiveness in vivo. Moreover, parameter relevance ranking allowed the segregation of study subjects into high and low responders. Due to the long intervention period the vitamin D response was not too prominent on the level of transcriptional activation. Therefore, we performed in the separate VitDbol trial a short-term but high dose stimulation with a vitamin D3 bolus. In PBMCs of VitDbol subjects we observed direct transcriptional effects on the selected VDR target genes, such as an up to 2.1-fold increase already one day after supplementation onset. In conclusion, both long-term and short-term vitamin D3 supplementation studies allow monitoring the vitamin D responsiveness of human individuals and represent new types of human in vivo vitamin D3 investigations.